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CHRIS CHEN: Okay, I Think We’Re Going to Try and Get Started

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CHRIS CHEN: Okay, I Think We’Re Going to Try and Get Started CHRIS CHEN: Okay, I think we’re going to try and get started. This digital clock scares me. So it means we have to be on time. So our next speaker is Milica Radisic, and she’ll tell you about her system. DR. RADISIC: Thank you very much, Chris. So I’ll tell you about our efforts to make healthy and diseased heart tissue in a chip. One of the main problems associated with making heart tissue in the lab is complexity in structure over many different length scales that then relates to function of the heart tissue. So if you want to have a contractile cardiac patch to be used to basically patch this part of myocardium that was damaged by myocardial infarction and in this particular image the patient had myocardial infarction that was so severe it made a hole in the person’s heart such that.the arrow is going through the hole; we have to make a patch that is contractile at the centimeter scale. If you look at the millimeter scale and we look at the myocardial ventricle, in the heart the myofibers are aligned and parallel. They’re elongated. But the orientation of the alignment changes as you go through the ventricle. Then again if we look at the micrometer scale, if you look at individual cells that are responsible for contraction, we see that these cardiomyocytes are all rod shaped, and they have very well developed sarcomeres: these registers of sarcomere. As sarcomeres contract, the whole cell will contract. And then on the nanometer scale, it’s the arrangement of sarcomeric proteins that enables the appropriate contraction of each unit of the cell. For us to get appropriate contractile function at the centimeter scale, we have to mimic structure over many different length scales. In engineering, we know this is a rather difficult problem. Not only that, but if you look into the heart, by volume it has very little extra cellular matrix. Most of the volume in the heart is occupied by cardiomyocytes. They make 90 percent of the volume of the heart, and they’re supported by very dense vascular network. This would be a cross section, and this would be a side view of the capillaries in the heart.’ About ten years ago, when I was training with Gordana and with Bob,we came up with this electrical stimulation approach where we would take cells, seed them into scaffolds. Thecells at that time were from neonatal rat hearts, and these resulting constructs we would cultivate between two parallel carbon electrodes connected to commercially available cardiac stimulator, and we would apply field stimulation pulses at about 1 Hertz that were super threshold so the tissue contracted with every pulse. As a result of this, we were able to get tissue with significantly improved functional properties, for example, higher maximum capture rate, lower excitation threshold, and these improved functional properties were a result of improved structure. So if you look at the cells in the stimulated construct, they’re all elongated. They’re all aligned in parallel like in the native heart. They have well developed sarcomeres, whereas the non-stimulated, the control tissues, had poorly developed sarcomeres and randomly alignedcells. These tissues, were about ten millimeters long; they were able to propagate electrical impulses which is one of the hallmarks of cardiac tissue, and we had significantly higher impulse propagation velocity in the stimulated group compared to the non-stimulated group. We know there are many barriers to placing these constructs into humans, and they’re related to safety of the cells that come from pluripotent stem cells. So in the meantime we thought that one of the ways we can enhance the field is by using these tissues as model systems for drug testing or to build healthy and diseased myocardium. So why is making engineered heart tissue and using them as a model better than using heart slices. We see a part of the answer to this question in the slide. First, this is a slice from a rat heart that was kept in the lab, cultivated for about two weeks. And you notice at the end of two weeks, most of the cells are dead whereas in the engineered heart tissue we can control very precisely how many cells stay alive and we have methods of keeping them alive. We know how many cells we seeded. And not only that, there is a shortage of donors that we could get the hearts from – human donors that we could get heart slices from. One of the first models that we used – that we looked at was a modelfor cell injection, and we did this with Peter Zandstra. The motivation for this was very large number of clinical studies that are currently underway and that are completed with injections of various progenitors of stem cells into hearts of patients. Although when people do meta analysis they record significant improvements in functional properties – for example, improvement in ejection fraction, this improvement is very small. It’s significant but very small – about 3 percent. So we thought that availability of a model of a cardiac tissue ex vivo could enhance some of this effort by enabling us to study how cells proliferate and integrate in a cardiac environment. For these studies we used embryonic stem cells, and they’re a good source because we can get many different stages from the same source. We can get undifferentiated cells or fully differentiated cardiomyocytes derived from embryonic stem cells. So in these studies we hypothesized that there is a committed cardiovasulcar progenitor, some were in between these two states that can give rise to cardiomyocytes and that can survive in cardiac environment very well. This work was published two years ago in PNAS, and I will just summarize it in two slides. So this is what happens to contraction when we inject fibroblasts. The tissue is barely able to contract. This is engineered heart tissue after injection of fibroblasts. When we inject mouse cardiomyocytes as a positive control, the tissue beats better. But when we inject ES-cell derived cardiovascular progenitors, we get much better beating. And these improved functional properties were a result of the ability of injected cells to basically spread along the tissue. They didn’t block the propagation. They actually – we’ve got very nice maps of impulse propagation throughout the tissue. And by new understanding we saw that the injected cells that were YFP-labeled were coupling with the host cardiomyocytes. And so not only by immunostaining but when we mapped calcium transients, we saw that basically injected cells were able to fire calcium transients at the same time and in synchrony with the host cells; this tells us that these cells were indeed coupled. One of the advantages of using engineered heart tissue as a model is that we can digest the tissue and we can prove – we can count the cells and prove that the cells stayed there, and we determined exactly how many cells we had. And each of these time points as we looked, we saw that the injected ESC derived cardiac progenitors were present, and this correlated with the improvement in function such as lowering of excitation threshold. More recently, we also used this engineered heart tissue as a model to study residual activity of undifferentiated cells. And so we found that when these undifferentiated cells are injected into the tissue or if they’re present in the mixtures of cells that are injected into tissue, if we wait long enough for about four weeks, we can get evidence of formation of tissues from all three germ layers. It means that there’s ectoderm, mesoderm and endoderm, and this is consistent to studies published by Murry’s group in vivo where they saw formation of teratoma upon injection of undifferentiated cells in the heart. I should also say at this point that there was – there is a controversy in the field what happens when you inject undifferentiated cells in the heart. Some people claim that if the dose is low enough, these cells will preferentially turn into cardiovascular lineages. In our in vitro system, basically no matter what the dose was, even with the lowest doses, we saw teratoma formation when we injected undifferentiated cells which is consistent with the reports from Murry’s lab. Also more recently we were able to develop a model that enables us to mimic some aspect of diabetic myocardium. Diabetes is on the rise in the developed world,partly due to sedentary life style, and diabetic patients show dysfunction of cardiomyocytes that is independent of any other underlying heart disease. So we looked at the levels of glucose and insulin found in the blood of diabetic patients and also diabetic mice. We formulated a condition that had high glucose concentration and low insulin concentration and we called this hyperglycemic. And then we also had a group that was hyperglycemic on insulin therapy and then something that would mimic a healthy control. By some molecular markers such as ratio of offbeat- myosin heavy chain to alpha- myosin heavy chain our engineered heart tissues were similar to the diabetic hearts. And when we placed these tissues on treatment with normally used diabetic drugs, we saw for example less cell death if you look at page 9 transcription in PID, and this is as expected. So where are we going next with this? You noticed in the previous slides that the tissue was relatively big. It was about the size of a penny or a cent.
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